Dataset Information

A novel AARS mutation in a family with dominant myeloneuropathy.

ABSTRACT:

Objective

To determine the genetic cause of neurodegeneration in a family with myeloneuropathy.

Methods

We studied 5 siblings in a family with a mild, dominantly inherited neuropathy by clinical examination and electrophysiology. One patient had a sural nerve biopsy. After ruling out common genetic causes of axonal Charcot-Marie-Tooth disease, we sequenced 3 tRNA synthetase genes associated with neuropathy.

Results

All affected family members had a mild axonal neuropathy, and 3 of 4 had lower extremity hyperreflexia, evidence of a superimposed myelopathy. A nerve biopsy showed evidence of chronic axonal loss. All affected family members had a heterozygous missense mutation c.304G>C (p.Gly102Arg) in the alanyl-tRNA synthetase (AARS) gene; this allele was not identified in unaffected individuals or control samples. The equivalent change in the yeast ortholog failed to complement a strain of yeast lacking AARS function, suggesting that the mutation is damaging.

Conclusion

A novel mutation in AARS causes a mild myeloneuropathy, a novel phenotype for patients with mutations in one of the tRNA synthetase genes.

SUBMITTER: Motley WW

PROVIDER: S-EPMC4442103 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Publications

A novel AARS mutation in a family with dominant myeloneuropathy.

Motley William W WW Griffin Laurie B LB Mademan Inès I Baets Jonathan J De Vriendt Els E De Jonghe Peter P Antonellis Anthony A Jordanova Albena A Scherer Steven S SS

Neurology 20150422 20

<h4>Objective</h4>To determine the genetic cause of neurodegeneration in a family with myeloneuropathy.<h4>Methods</h4>We studied 5 siblings in a family with a mild, dominantly inherited neuropathy by clinical examination and electrophysiology. One patient had a sural nerve biopsy. After ruling out common genetic causes of axonal Charcot-Marie-Tooth disease, we sequenced 3 tRNA synthetase genes associated with neuropathy.<h4>Results</h4>All affected family members had a mild axonal neuropathy, a ...[more]

PMID: 25904691

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Project description:BackgroundPrimary ciliary dyskinesia (PCD) is a clinically heterogeneous group of autosomal or, less frequently, X-chromosomal recessive inheritance syndrome of motile cilia dysfunction characterized by neonatal respiratory distress, oto-sino-pulmonary disease, infertility and situs inversus. Recently, type 43 PCD (CILD43, OMIM#618699) was established by autosomal-dominant loss-of-function mutations identified in Forkhead box J1 (FOXJ1). However, the functional validation of FOXJ1 mutations in humans and mice has not been fully performed. Here we studied a three-generation family with heterotaxy and proband with complex congenital heart disease (CHD).MethodsWe performed whole-exome sequencing to investigate the causative variant of this family and generated gene knock-in mice carrying the human equivalent mutation by homologous recombination. Then, microscopy analysis was used to characterize the phenotype and ciliary ultrastructure of the model. Effects of the variant on heart anomaly were preliminarily explored through transcriptome sequencing.ResultsA novel heterozygous deletion variant (c.1129delC/p.Leu377Trpfs*76) of FOXJ1 was discovered that exerts a dominant-negative effect (DNE) in vitro. Notably, both homozygous (Foxj1c.1129delT/c.1129delT) and heterozygous (Foxj1+/c.1129delT) mice developed situs inversus, hydrocephalus and showed a disruption of trachea cilia structure, whereas these abnormalities were only observed in previously reported Foxj1-/-, not Foxj1+/- mice. Thus, a more severe phenotype and higher expressivity of our mouse model further indicated the DNE of this mutation. Meanwhile, several cardiomyopathy-related genes were differentially expressed in the homozygous Foxj1 knock-in mouse hearts, pointing to a probable function in cardiac pathology.ConclusionsOverall, our study results showed that c.1129delC mutation in FOXJ1 was regarded as the cause of situs inversus in this family and this mutant showed a capacity of DNE over wild-type FOXJ1, causing more serious consequences than the allelic deletion of Foxj1.

Dataset Information

A novel AARS mutation in a family with dominant myeloneuropathy.

Objective

Methods

Results

Conclusion

Publications

A novel AARS mutation in a family with dominant myeloneuropathy.

Similar Datasets

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